Combinations of retigabine and sodium channel inhibitors or sodium channel-influencing active compounds for treating pains

ABSTRACT

The invention relates to pharmaceutical combinations of retigabine and sodium channel inhibitors for treating, pains which are accompanied by an increase in muscle tone.

This application is a continuation of U.S. application Ser. No.10/727,655, filed Dec. 5, 2003, which claims priority to GermanApplication Serial No. DE 10349729.3, filed Oct. 3, 2003, each of whichthe entire contents are incorporated herein by reference.

The invention relates to pharmaceutical combinations of retigabine andsodium channel inhibitors for treating pains which are accompanied by anincrease in muscle tone.

A number of different painful diseases are accompanied by an increase inskeletal muscle tone. In some cases, the pain generation is elicited byjoint inflammations, and a painful body posture, which is frequentlyaccompanied by painful muscle spasms, develops as a consequence. Thetreatment of these diseases includes benzodiazepines, for example;however, these compounds possess a marked potential for addiction andthis limits their use. Frequently, treating the basic disease, e.g. therheumatoid inflammation, does not result in corresponding, satisfactorytherapeutic successes. For this reason, the additional administration ofanalgesics and/or skeletal muscle relaxants is often indicated.

In clinical practice, centrally acting muscle relaxants are used foralleviating abnormally elevated muscle tone in patients who aresuffering from painful muscle spasms and/or rigidity in association withrheumatoid diseases or spasms in connection with neurological diseases.While a number of appropriate active compounds are available on themarket, their clinical efficacy is frequently questionable or elselimited by undesirable side effects.

The Na⁺ channel-inhibiting substances constitute one class of theseactive compounds. Evidence exists that these substances are able torelieve an increase in muscle tone. It has been shown that, inclinically relevant concentration, propofol has a marked inhibitoryeffect on the sarcolemma sodium channels. This mechanism couldcontribute to reducing muscle tone (Haeseler et al., Anesth Analg 2001;92:1192-8). It has also been shown that inhibiting the Na⁺ channelsinhibits neurotransmitter release from the presynaptic termini(Obrenovitch, Int Rev Neurobiol 1997; 40:109-35). The neuroprotectiveactive compound riluzole is a sodium channel inhibitor and anantiexcitotoxic substance which is used for treating amyotrophic lateralsclerosis. Kennel et al. (J Neurol Sci 2000; 180:55-61) have recentlyshown that riluzole significantly delays the onset of the paralysis, andretards the progress of the functional parameters connected to musclestrength, in a mouse model of motoneuron disease. In a mouse model ofheritable myotonia (De Luca et al., J Pharmacol Exp Ther 1997;282:93-100), metilexin, an antiarrhythmic and antimyotonic substance,blocks the skeletal muscle sodium channels (Duranti et al., Eur J MedChem 2000; 35:147-56) and relieves the hyperexcitability of the skeletalmuscles. That the function of the skeletal muscle sodium channels isimportant in maintaining normal tone is supported by the fact that ithas been possible to connect mutations in the gene for the α-subunit ofthe voltage-induced Na⁺ channel (SCN4A) with inherited, nondystrophicmyotonia. Interestingly, the myotonia resolved dramatically onadministration of the Na⁺ channel-inhibiting substance flecainide(Rosenfeld et al., Ann Neurol 1997; 42:811-4).

Tolperisone is a centrally acting muscle relaxant which is relativelywell tolerated clinically. To date, relatively few publications havedealt with the mechanism of action of tolperisone-like compounds.Tolperisone suppresses transmission of the spinal segment reflex andeffectively reduces C fiber-induced transmission in the afferent nervesboth in vivo and in vitro (Farkas et al., Neurobiology 1997; 5:57-58).As compared with lidocaine, a local anesthetic, the substance has lessof a blocking effect on transmission in the A fibers. It characteristiceffect is that of strongly inhibiting the monosynaptic and polysynapticspinal reflexes (Farkas et al. Neurobiology 1997; 5:57-58, Kocsis etal., Acta Pharm Hung 2002; 72(1):49-61, Okada et al., Jpn J Pharmacol2001; 86:134-136). In rats, Ono et al. (J Pharmacobio Dynam 1984;7:171-178) showed that tolperisone exhibits an effect like that of alocal anesthetic (“membrane-stabilizing”) both in motor neurons and inprimary afferents in vivo as well as on the peripheral nerves in vitro.The effect of tolperisone appears to be similar to that of lidocaine,which is known to act as an inhibitor of voltage-dependent sodiumchannels (Strathmann 2002,www.ifap-index.de/bda/hausarzt/19-2002/6483.pdf). It has been shown thattolperisone, like lidocaine, blocks the tetrodotoxin (TTX)-sensitive andTTX-resistant currents and in this way gives rise to an inhibitoryeffect on both types of voltage-dependent sodium channels (Bastigkeit,MMW-Forschr Med 2000; 142:50-51, Farkas et al., 2000,http://www.asso.univparis5.fr/ewcbr/Francais/EWCBR2000/Abstracts/ABST126.htm;Kocsis et al., Acta Pharm Hung 2002; 72(1):49-61). It is probable thatthe mechanism of action of tolperisone in this connection differssomewhat from that of lidocaine. In addition, evidence exists thattolperisone lowers sodium permeability. This effect could be responsiblefor the excitability-reducing effect of tolperisone and consequently forthe antispastic effect which has been recorded in clinical observations(Hinck and Koppenhofer, Gen Physiol Biophys 2001; 20:413-29). Inaddition, voltage-clamp experiments performed on snail neurons showedthat tolperisone and its analogs inhibit voltage-dependent calcium flows(Novalies-Li et al., Eur J Pharmacol 1989; 168:299-305). Tolperisoneanalogs such as eperisone and silperisone exhibited similar behavior inelectrophysiological experiments. Thus, it has been shown, for example,that silperisone reduces sodium permeability (During and Koppenhofer,Gen Physiol Biophys 2001; 20:157-73). It can be concluded from this thatthese substances might be able to reduce spastic skeletal muscle tone.

It has furthermore been shown, in clinical studies, that thesesubstances are able to alleviate painful spasms which are associatedwith neurological or rheumatoid diseases. The effective employment oftolperisone in treating muscle spasms has been reported (Pratzel et al.,Pain 1996; 67:417-25). Some derivatives of tolperisone, e.g. eperisone,also exhibited efficacy in the treatment of painful muscle spasms (Bose,Methods Find Exp Clin Pharmacol 1999; 21:209-13). Under certainpathological conditions, neurons are in a state of continuousdepolarization, resulting in their sodium channels reacting moresensitively to the inhibitory effects of particular substances. Thisprovides the possibility of alleviating muscle spasms and pain whilepreserving a favorable side-effect profile. More recent data indicatethat tolperisone and its analogs exert selectively inhibitory effects onvoltage-dependent sodium channels. This mechanism could be responsiblefor their spinal reflex-suppressing and muscle-relaxing effect. Inaddition, this property could produce the pain-alleviating effect which,because of the small differences which have been observed, could, incontrast to lidocaine, be free of side effects.

The potassium channel openers constitute another class ofmuscle-relaxing substances.

The substances include retigabine, for example. In in vitro analyses, itwas shown that retigabine exerts multiple effects on sites which areconnected with neurotransmission and membrane excitability. The primarymechanism of action appears to be based on a potassium channel openingwhich leads to marked stabilization of slightly depolarized, i.e.hyperexcitable cells and can result in an elevated skeletal muscle tonebeing reduced (Rundfeldt and Netzer, Neurosci Letters 2000, 282:73-6).

Flupirtine is another representative of this substance class, whichbelongs to a class of triaminopyridines and which is used as a nonopioidanalgesic possessing muscle-relaxing properties. It has been shown thatflupirtine reduces skeletal muscle tone when it is used in doses whichare comparable to those of the antinociceptive effect (Nickel et al.,Arzn Forsch/Drug Res 1990a; 40:909-11).

More recent investigations demonstrate that flupirtine activatesvoltage-independent potassium channels (Kornhuber et al., J NeuralTransm 1999; 106:857-67). This potassium channel-opening effect offlupirtine could be responsible for its analgesic and skeletalmuscle-relaxing effect.

The prior art which has been described shows clearly that, while thereare a number of substances which are used for treating pain conditionsinvolving an increase in muscle tone, undesirable side effectsfrequently set limitations to their use. For example, at higher doses,flupirtine exhibits neurotoxic effects such as drowsiness andcoordination disturbance. While tolperisone does not exhibit any severeundesirable side effects, its activity and the duration of its effect inconnection with muscle relaxation are not satisfactory, possibly due toits relatively low bioavailability and its short half-life in humans(Ito et al., Arch Int Pharmacodyn Ther 1985; 275:105-22), Matsunaga etal., Jpn J Pharmacol 1997; 73:215-20).

The object of this invention is therefore that of providing apharmaceutical for treating pains which are accompanied by an increasein muscle tone, which pharmaceutical exhibits less serious side effectswhile having a comparable efficacy or else exhibits a higher activity atthe same dose.

According to the invention, it was possible to achieve this by means ofthe novel combination of retigabine and a sodium channel inhibitor.

It was possible to show that the combination of sodiumchannel-inhibiting or -influencing active compounds and potassiumchannel openers increases the muscle-relaxing effect.

The following may, for example, be employed as Na⁺ channel-inhibiting or-influencing substances: tolperisone and its analogs eperisone andsilperisone, riluzole, propafenone, lidocaine, flecainide and metixen,as well as their pharmaceutically utilizable salts.

Particular preference is given, in this connection; to the combinationof tolperisone, or its analogs, and retigabine, or theirpharmaceutically utilizable salts. The combination according to theinvention makes the treatment of pains which are accompanied by anincrease in muscle tone more effective and more reliable. Thecombination of Na-channel inhibiting or -influencing substances andretigabine leads either to an increase in the therapeutic effect or animprovement in tolerability. For example, it has been shown that Nachannel-inhibiting or -influencing active compounds such as tolperisonecan amplify the muscle-relaxing effect of retigabine, and vice versa.However, what is surprising, and unexpected for the skilled person, is,in particular, the effect that tolperisone superadditively amplifies theskeletal muscle-relaxing effect of retigabine and vice versa. Bycontrast, tolperisone does not amplify the side effects of retigabine.

The combination of the two substances can be used for treating pains inconnection with diseases of the skeletal musculature which areaccompanied by hypermyotonia and restricted mobility, in particularthose which are elicited by injuries to the spinal cord, osteoporosis,arthritis and ankylosis/spastic conditions. It is also effective inconnection with pains of the following origin: lumboischial pains,neurolathyrism, arthritis, diseases of the peripheral circulatorysystem, climacteric muscular and vascular complaints, trismus, myogenicheadaches, rheumatic diseases which are accompanied by musclehypertonia, spasms, pain, inflammatory symptoms and restricted mobility,and multiple sclerosis, and in the postoperative treatment of traumaticpatients and for treating lower spastic paraparesis syndrome: lowerparaspasm, transverse myelitis, multiple sclerosis, heritable inferiorspastic paraplegia (Stuempel paraplegia), disturbances of the spinalblood circulation, cerebral paralysis involving lower spastic paresis,tetraparesis in connection with cervical myelopathy, vertebraldysplasia, tension headache and cervical brachialgia.

The combinations of Na⁺ channel-inhibiting or -influencing activecompounds and retigabine, and of their pharmaceutically utilizablesalts, can be administered in all oral, enteral, rectal, lingual,intravenous, intramuscular, intraperitoneal, transdermal, subcutaneousor intracutaneous administration forms. Examples of preferred oraladministration forms are tablets, film-coated tablets, sugar-coatedtablets, hard gelatin capsules, soft gelatin capsules, chewing tablets,sucking tablets, syrup, controlled release preparations (for exampledual formulation, delayed-release formulation), pellets, chewing tabletsor soluble granules. Examples of other suitable administration formsare: solutions for injection, suspensions, suppositories, creams,ointments, gels, transdermal administration forms and subcutaneous orintracutaneous implants.

The substances can be administered simultaneously, consecutively or in afixed combination. They can be administered together in oneadministration form or in two administration forms which can beidentical or different. They can be administered simultaneously orconsecutively, either briefly one after the other or at longer timeintervals, for example retigabine in the evening and tolperisone in themorning.

The active compounds can be administered between 1 and 8 times daily, inan adequate quantity to achieve the desired affect. The active compoundsare preferably administered from once to four times daily.

The daily dose should correspond to the approved quantities of thesubstances which are in each case employed in the combination.

1. The use of retigabine or its pharmaceutically utilizable salts incombination with sodium channel-inhibiting or -influencing substances,or of their therapeutically utilizable salts, for treating pains whichare accompanied by an increase in muscle tone.
 2. The use as claimed inclaim 1, wherein the sodium channel-inhibiting or -influencingsubstances employed are tolperisone or its analogs eperisone orsilperisone, or riluzole, propafenone, lidocaine, flecainide or metixen,or their pharmaceutically utilizable salts.
 3. The use as claimed inclaim 1, wherein the sodium channel-inhibiting or -influencingsubstances employed are tolperisone or its analogs, such as eperisone orsilperisone, or their pharmaceutically utilizable salts.
 4. The use ofretigabine in combination with tolperisone or its analogs, such aseperisone or silperisone, or their pharmaceutically utilizable salts,for treating pains which are accompanied by an increase in muscle tone.5. The use as claimed in claim 1, for treating pains associated withneuralgias.
 6. The use as claimed in claim 1, for treating painsassociated with arthritis and arthrosis.
 7. The use as claimed in claim1, for treating pains associated with chronic or episodic tensionheadache.
 8. The use as claimed in claim 1, for treating painsassociated with lower spastic paraparesis syndrome (e.g. lowerparaspasm, transverse myelitis, multiple sclerosis, heritable inferiorspastic paraplegia (Stuempel paraplegia), disturbances of the spinalblood circulation and cerebral paralysis involving lower spasticparesis).
 9. The use as claimed in claim 1, for treating painsassociated with tetraparesis in connection with cervical myelopathy,cervical brachialgia or vertebral dysplasia.
 10. The use as claimed inclaim 1, for treating pains associated with Parkinson's disease.
 11. Theuse of retigabine or its pharmaceutically utilizable salts incombination with sodium channel-inhibiting or -influencing substances,and of their therapeutically utilizable salts, for producing amedicament for oral, rectal, intravenous, transdermal or subcutaneous orintracutaneous administration for treating pains which are accompaniedby an increase in muscle tone.